Total synthesis of (-)-Przewalskin B

Article abstract of DOI:10.1021/ol102593r

The first total synthesis of (-)-Przewalskin B has been accomplished with an intramolecular nucleophilic acyl substitution (INAS) reaction and an intramolecular aldol condensation as key steps.

Full text of DOI:10.1021/ol102593r

ORGANIC
LETTERS
2
011
Vol. 13, No. 2
73-175
Total Synthesis of (-)-Przewalskin B
1
†
Jiyue Zheng, Xingang Xie, Changgui Zhao, Yongping He, Huaiji Zheng,
†
†
†
†
†
Zhen Yang, and Xuegong She*
,†,‡
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, People’s Republic of China, and State Key
Laboratory for Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China
shexg@lzu.edu.cn
Received October 26, 2010
ABSTRACT
The first total synthesis of (-)-Przewalskin B has been accomplished with an intramolecular nucleophilic acyl substitution (INAS) reaction and
an intramolecular aldol condensation as key steps.
Przewalskin B (1, Figure 1), a novel diterpenoid isolated from
a Chinese medicinal plant SalVia przewalskii by Zhao et al.
in 2007, was found to exhibit modest anti-HIV-1 activity
of diester 4 which could easily be prepared from diiodide 5
and malonate derivative 6 by an alkylation reaction.
1
with EC50 ) 30 µg/mL. The structure of 1 was revealed by
means of comprehensive NMR spectroscopic analysis and
a single-crystal X-ray study to have a fused tetracyclic
skeleton containing a five-membered spiro ring and R-hy-
droxy-ꢀ-ketone lactone moieties. Due to its biological profile
and intriguing structure, Przewalskin B (1) represents an
attractive target for the synthetic community. In this com-
munication, we report the first total synthesis of (-)-
Przewalskin B (1).
Figure 1. Structure of Przewalskin B (1).
Our retrosynthetic analysis for Przewalskin B (1) is
outlined in Scheme 1. It was our view that the γ-lactone
ring (D) of 1 and its tertiary OH could be established from
the spirocyclic enone 2 at the last stage. For enone 2, its
five-membered spiro ring (C) could be constructed from ester
4
Our synthesis started with the known chiral alcohol 7
which was readily prepared from the commercially available
,4-dimethyl-2-cyclohexenone in four steps (Scheme 2).
4
3
via an intramolecular aldol condensation. Bicyclic ester 3
Following iodination of alcohol 7, diiodide 5 was obtained
could be realized via an intramolecular nucleophilic acyl
in 96% yield. For the required diester 6, it was prepared from
2
3
substitution (INAS) reaction on the diastereotopic groups
5
1
-bromo-4-methylpentan-2-one 8 and diethyl malonate by
an alkylation coupling followed by acetal protection in 90%
yield for two steps. With 5 and 6 in hand, their coupling
reaction was performed to afford the INAS reaction precursor
4 in 85% yield.
†
Lanzhou University.
Chinese Academy of Sciences.
‡
(
1) Xu, G.; Hou, A.; Zheng, Y.; Zhao, Y.; Li, X.; Peng, L.; Zhao, Q.
Org. Lett. 2007, 9, 291–293.
1
0.1021/ol102593r  2011 American Chemical Society
Published on Web 12/09/2010

at 0 °C for 40 min, gave a 2:1 inseparable mixture of
a/9b in a 55% combined yield (Scheme 3). Fortunately,
9
Scheme 1. Retrosynthetic Analysis
Scheme 3. Synthesis of 11
Scheme 2. Synthesis of the Key INAS Reaction Precursor 4
protection of 9a and 9b as MOM ethers gave a separable
mixture of 3 and 10 in 60% and 30% yield, respectively.
The relative stereochemistry of the major isomer 3 was
confirmed by single-crystal X-ray study of its derivative
1
1, which could be obtained in 88% yield for the two
steps.
With the key bicyclic intermediate 3 in hand, we
continued to construct the CD ring system of 1 to finish
the total synthesis. As depicted in Scheme 4, partial
reduction of ester 3 with DIBAL-H followed by removal
of the acetal protecting group gave 1,4-diketone 13 which
underwent an intramolecular aldol condensation to afford
tricyclic enone 2 in 71% overall yield for three steps.
Subsquently, treatment of ketone 2 with LDA and ethyl
The key INAS reaction was then performed. Treatment
of vinyl iodide 4 with 1.0 equiv of n-BuLi in THF at -100
6
°
C for 1 h, followed by Luche reduction (CeCl
3
, NaBH
4
)
7
cyanoformate afforded the acylation product 14 as a
(
2) For related INAS reaction, see: (a) Wang, B.; Zhong, Z.; Lin, G.
single diastereoisomer in 96% yield. Deprotection of 14
followed by a DBU-promoted lactonization generated the
tetracyclic ꢀ-ketone lactone 16 in 76% yield. Finally,
Org. Lett. 2009, 11, 2011–2014. (b) Chau, C. M.; Liu, K. M. Org. Biomol.
Chem. 2008, 6, 3127–3134. (c) Lage, S.; Villaluenga, I.; Sotomayor, N.;
Lete, E. Synlett 2008, 20, 3188–3192. (d) Faltz, H.; Bender, C.; Liebscher,
J. Synthesis 2006, 17, 2907–2922. (e) Faltz, H.; Bender, C.; W o¨ hrl, B. M.;
Vogel-Bechmayr, K.; H u¨ bscher, U.; Ramadan, K.; Liebscher, J. Eur. J.
Org. Chem. 2004, 3484–3496. (f) Calaza, M. I.; Hupe, E.; Knochel, P. Org.
Lett. 2003, 5, 1059–1061. (g) Otto, A.; Liebscher, J. Synthesis 2003, 8,
8
treatment of 16 with LDA and Davis’oxaziridine 17 at
-
78 °C for 0.5 h gave compound 1, (-)-Przewalskin B,
1
3
4
8
209–1214. (h) Swaleh, S.; Liebscher, J. J. Org. Chem. 2002, 67, 3184–
193. (i) Ollero, L.; Castedo, L.; Dom ´ı nguez, D. Tetrahedron 1999, 55,
445–4456. (j) Kratzel, M.; Mabhoti, R. J. Heterocyclic Chem. 1998, 35,
71–874. (k) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.; Katoh, T.;
(4) Jan, N.; Liu, H. Org. Lett. 2006, 8, 151–153.
(5) Dickschat, J. S.; Reichenbach, H.; Wagner-Dobler, I.; Schulz, S. Eur.
J. Org. Chem. 2005, 4141–4153.
Terashima, S. Tetrahedron Lett. 1998, 39, 6911–6914. (l) Paleo, M. R.;
Castedo, L.; Dom ´ı nguez, D. J. Org. Chem. 1993, 58, 2763–2767. (m) Flann,
C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115–6118.
(6) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(7) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1990, 70,
256.
(
3) For an excellent review of stereoselective synthesis using diaste-
(8) Davis, F. A.; Chaltophadhyay, S.; Towson, T. C.; Lol, S.; Reddy,
T. J. Org. Chem. 1988, 53, 2087–2089.
reotopic groups, see: Hoffmann, R. W. Synthesis 2004, 2075.
174
Org. Lett., Vol. 13, No. 2, 2011

Scheme 4. Total Synthesis of (-)-Przewalskin B
in 81% yield. H and 13C NMR spectra and other physical
data of our synthetic compound 1 were all in good
agreement with those of the natural (-)-Przewalskin B.
In summary, the first total synthesis of (-)-Przewalskin
B has been achieved in 15 steps with 8.1% overall yield
starting from the commercially available 4,4-dimethyl-2-
cyclohexenone, involving an INAS reaction, intramolecular
aldol condensation, and lactonization as key steps to furnish
the unique fused tetracyclic skeleton of the natural product.
1
Acknowledgment. We are grateful for the generous
financial support by the MOST (2010CB833200) and the
NSFC (20872054, 20732002) and Program 111.
Supporting Information Available: Experimental pro-
cedures and compound characterization for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102593R
Org. Lett., Vol. 13, No. 2, 2011
175